ES2235955T3 - NEUVES DERIVED FROM PIRIMIDINA-2,4,6-TRIONA, PROCESSES FOR ITS PRODUCTION AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS. - Google Patents

Abstract

Compounds of the ** formula ** in which R1 means a phenoxy moiety, in which the phenyl group may be substituted by one or more halogen atoms, hydroxy groups, C1-C6 alkoxy, C1-C6 alkyl, cyano or nitro ; and R2 means pyrimidine, pyrazine or its N-oxides or phenyl substituted by -SO2NR3R4, wherein R3 and R4 are the same or different and mean hydrogen; C1-C6 alkyl, straight or branched chain, which may be substituted once or several times by OR, N (CH3) 2 or which may be interrupted by oxygen; or means COR5, in which R5 is an alkyl group

Description

New derivatives of pyrimidine-2,4,6-trione, processes for their production and pharmaceutical agents containing these compounds.

This invention relates to new derivatives of pyrimidine-2,4,6-trionas 5,5-disubstituted These compounds have a marked antitumor and antimetastatic activity.

In a normal tissue there is a balance between synthesis and degradation The matrix or extracellular structure is degrades by action of proteinases that belong to at least three structure metalloproteinase groups. They are collagenous, gelatinases and stromelysins. Normally there are no inhibitors specific to these catabolic enzymes, for example α2 macroglobulins and TIMPs (= tissue inhibitor of metalloproteinases (MMP)), so that a excessive degradation of extracellular structure. Adamalisins They are a related group of proteinases.

A prominent representative of the group of adamalisins is the TACE (TNF-?-Converting enzyme).

At least 17 different but very homologous MMP species have been characterized, including interstitial fibroblast collagenase (MMP-1, HFC), neutrophil collagenase (MMP-8, HNC), two gelatinases, stromelysins (for example HSL -1) and HPUMP (see the recent review by Birkedal-Hansen, H., Moore, WGI, Bodden, MK, Windsor, LJ, Birkedal-Hansen, B., DeCarlo, A., Engler, JA, Critical Rev. Oral Biol. Med. 4 , 197-250, 1993). These proteinases have in common a large number of structural and functional features, but differ somewhat in their substrate specificity. Only HNC and HFC are capable of breaking a single bond of native triple helix type I, II and III collagen, producing fragments that are 3/4 and 1/4 of the length of the native chain. This decreases the melting point of collagens and makes them accessible to further attack by enzymes of structural degradation.

However, excessive degradation and uncontrolled of this structure or matrix is characteristic of many pathological conditions, eg the clinical picture of arthritis rheumatoid, osteoarthritis and multiple sclerosis; the formation of tumor metastases, corneal ulceration, inflammatory diseases and invasion and diseases of bones and teeth

It can be assumed that the pathogenesis of these clinical conditions can be favorably influenced by the administration of structural metalloproteinase inhibitors. A large number of compounds are currently known from the technical literature (see, for example, the review article by DD Levy, AM Ezrin, Emerging Drugs 2 , 205-230, 1997; M. Whittaker, P. Brown, Curr. Opin Drug Discovery Dev. 1 (2), 157-164, 1998) or described in the patent literature, mainly with a hydroxamic acid moiety, or a thiol or phosphine group in the form of a zinc fixation group (see p. eg WO-A-9209563 from Glycomed; EP-A-497 192 from Hoffmann-LaRoche; WO-A-9005719 from British Biotechnology; EP-A-489 577 from Celltech; EP-A-320 118 from Beecham; US- A-4595700 from Searle; WO 97/20824 from Agouron Pharmaceuticals; WO 96/15096 from Bayer Corporation, among others).

Some of these compounds have a great activity as structural metalloproteinase inhibitors (or of matrix), but its oral availability is very low. In addition, such compounds often exhibit a broad spectrum inhibition of metalloproteinases, which may be associated with side effects Annoying and toxic.

The derivatives of the pyrimidine-2,4,6-trione have described genetically in the document EP-0869947 as metalloproteinase inhibitors structural. However, there is still a great demand for new compounds that have low toxicity, have no effect side effects and have a marked inhibitory activity against metalloproteinases, especially as possible candidates for chronic treatment against tumor growth and against metastasis.

It has now been found that new derivatives claimed of pyrimidine-2,4,6-trione possess a better activity as structural metalloproteinase inhibitors that the compounds claimed in the document EP-0869947 and also present a good oral availability

The present invention thus relates to compounds of the general formula I

one

in the that

R 1 means a phenoxy moiety, in which the phenyl group may be substituted by one or more atoms of halogen, hydroxy groups, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, cyano or nitro; the Preferred substitutions take place in position "for" and / or "goal" with one or two substituents,

R2 means pyrimidine, pyrazine or its N-oxides or phenyl substituted by -SO 2 NR 3 R 4, in which R 3 and R 4 are same or different and mean hydrogen; I rent C 1 -C 6, straight or branched chain, which it can be substituted once or several times by OH, N (CH 3) or that may be interrupted by oxygen; or they mean COR5 {,} wherein R 5 is an alkyl group that may be substituted by NH2.

The present invention also encompasses salts or pharmaceutically acceptable prodrugs of the compounds of the formula I as well as the use of these compounds to make agents Pharmacists

Halogen means fluorine, chlorine, bromine, iodine, preferably chlorine or bromine.

If the compounds of the general formula I contain one or more asymmetric carbon atoms, the compounds of the general formula I which are optically active are also object of the present invention.

The compounds of the general formula I can synthesized by well known procedures, preferably through a process in which the compounds of are reacted the general formula II

2

in which R_ {1} has the meaning defined before and T means a leaving group, by example Hal or OSO2R3, Hal means chlorine, bromine or iodine and R 3 means an aryl or methyl moiety, with a compound of the General Formula III

3

in which R2 has the meaning defined above and optionally become pharmaceutically salts acceptable.

The compounds of the general formula II can be synthesized in a manner similar to that described in procedures known in the technical literature. For example, pyrimidine-2,4,6-trionas brominated in position 5 can be synthesized by reacting the appropriate dialkyl bromomalonates with urea (eg Acta Chim. Acad. Sci. Hung. 107 (2), 139 , 1981). The corresponding brominated or chlorinated compounds of the general formula II can be obtained by reaction of the pyrimidine-2,4,6-trionas substituted by R 1 -phenyl in position 5 by bromine (similar to that described in J. Prakt. Chemie 136 , 329, 1933; or in J. Chem. Soc. 1931 , 1870) or with sulfuryl chloride (J. Chem. Soc. 1938 , 1622) or with N-bromo-succinimide or with similar brominating agents. These procedures are also described in EP-0869947.

The amines of formula III are products commercial or are usually known by the bibliography technique or can be synthesized by methods similar to those described in the experimental part.

The pyrimidine-2,4,6-trions of the formula II in which T means hydrogen can be obtained according to known methods, reacting malonic acid esters with urea (see for example J. Med. Chem. 10 , 1078 , 1967) or Helvetica Chim. Minutes 34 , 459, 1959; Pharmacie 38 (1), 65, 1983; or EP-0869947). The reactions are generally carried out in alcohols, for example methanol, ethanol or butanol, in the presence of an appropriate sodium alcoholate, at a temperature between 40 ° C and 100 ° C.

The esters of malonic acid required for get pyridine-2,4,6-trionas se known by the bibliography or can be obtained according to known procedures of said bibliography. A process convenient to obtain malonic acids, in which R1 has the meaning defined above, is described in the following scheme:

4

Examples of these reactions can be found in Houben-Weyl, vol. E5 / 2, J. Org. Chem. 46 , 2999, 1981 and in Arch. Pharm. 323 , 579, 1990.

The compounds of the general formula I can have one or more chiral centers and may in that case be present in a racemic form or in an optically active form. Racemates can be separated according to methods already known in the enantiomers. The diastereomeric salts, which can be separated by crystallization, they can be preferably formed from racemic mixtures by reaction with an optically active acid, eg D- or L-tartaric acid, the acid Mandelic, malic acid, lactic acid or acid camphor sulfonic acid or with an optically active amine, eg the D- or the L-? -Phenyl-ethylamine, ephedrine, quinidine or cinconidine.

Alkaline salts, alkaline earth salts, eg Ca or Mg salts, ammonium salts, acetates and Hydrochlorides are mainly used as salts pharmaceutically acceptable and can be obtained by the method usual, eg assessing compounds with inorganic bases or organic, such as sodium hydroxide, aqueous ammonia, C 1 -C 4 alkylamines, eg triethylamine, or with hydrochloric acid. The salts are normally purified by reprecipitation in water / acetone.

The new compounds of formula I and salts thereof according to the invention can be administered via enteral or parenteral in a liquid or solid form. In this context all the usual forms of administration, for example tablets, coated tablets, syrups, solutions, suspensions, etc. As injection medium is used preferably water containing additives, for example stabilizers, solubilizers and buffers common in solutions injectable

Such additives are eg tartrate buffers and citrate, complexing agents (eg acid ethylenediaminetetraacetic and non-toxic salts thereof), high molecular weight polymers (eg poly (ethylene oxide) liquid) to regulate viscosity. Excipient substances liquids for injectable solutions have to be sterile and They are preferably dispensed in ampoules. Excipient substances solid are eg starch, lactose, handyman, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (for example acid stearic acid), jellies, agar, calcium phosphate, stearate magnesium, animal and vegetable fats, solid polymers of high molecular weight (for example polyethylene glycols); the preparations suitable for oral application may also contain Flavors and sweeteners.

The dosage will depend on various factors, for example the mode of administration, the compound, the age and / or the individual's state of health The doses to be administered daily they will be between 10 and 1000 mg / person, preferably between 100 and 500 mg / person and can be taken at one time or distributed in Several administrations.

The prodrugs of the compounds of the invention are those that become " in vivo " in the pharmacologically active compound. The most common prodrugs are carboxylic acid esters.

Example 1 5- (4- (4-Chloro-phenoxy) -phenyl) -5- (4-pyrimidin-2-yl-piperazine) -pyrimidine-2,4,6-trione TO) 1- (4- (4-Chloro-phenoxy) -phenyl-ethanone

It dissolves the 4-Fluoro-acetophenone (24.4 g) in dimethylformamide (180 ml), 4-chlorophenol is added (22.8 g) and potassium carbonate (29.5 g). The mixture is heated to reflux with stirring for 7 hours. The mixture is cooled, it is dilute with water and extract with methylene chloride. The phase is washed organic with water, dried and concentrated, obtaining 38 g of a crystalline solid, m.p. 66-68 ° C.

B) 2- (4- (4-Chloro-phenoxy) -phenyl) -morpholin-4-yl-ethane-thione

12.4 g of the product obtained by the previous procedure with sulfur (4 g) and morpholine (8.8 ml). Be heat the mixture at 150 ° C for 2 h, cool in a bath of ice and treated with ethanol (20 ml) for 30 minutes. They are collected the crystals precipitated and recrystallized from ethanol, obtaining 13 g of the epigraph compound, m.p. 104-105 ° C.

C) acid 4- (4-Chloro-phenoxy) -phenyl) -acetic acid

10.4 g of the heat is heated at 130 ° C for 8 h compound obtained in stage B together with 50% sulfuric acid (200 ml). The reaction mixture is cooled to room temperature, It is diluted with water (300 ml) and extracted with ethyl acetate. Be wash the organic phase with water and then extract with a solution 2N sodium carbonate. The aqueous phase is acidified with acid. diluted hydrochloric, ethyl acetate is added, the phase is separated organic, dried and concentrated, obtaining 5.1 g of a residue brownish, from m.p. 98-100 ° C.

D) (4- (4-Chloro-phenoxy) -phenyl) -acetate of methyl

5.1 g of the product of stage C are dissolved in methanol (50 ml). The solution is cooled to -10 ° C and treated with thionyl chloride (3 ml) and then heated to reflux for 1 hour. The reaction mixture is concentrated by evaporation. and the residue is dissolved in ether. The ether phase is washed with water, it is dried and concentrated, obtaining 5.1 g of a colored oil reddish brown.

AND) 2- (4- (4-Chloro-phenoxy) -phenyl) -malonate dimethyl

A suspension of at room temperature is treated sodium hydride (350 mg) in dimethyl carbonate (10 ml) with the product obtained in step D. The mixture is heated to 90 ° C for 1 hour, cool and pour over water-ice and extracted with methylene chloride. Be dry the extract and concentrate by evaporation, obtaining 5.7 g of the epigraphized compound in the form of oil.

F) 5- (4- (4-Chloro-phenoxy) -phenyl) -pyrimidine-2,4,6-trione

Sodium (800 mg) is dissolved in ethanol (80 ml). TO this solution is added urea (1.65 g) and a solution of the compound obtained in the previous stage in ethanol (5.5 g). It heats up mixture at reflux for 3 hours, cooled to room temperature, it is treated with ice-water (100 ml) and acidified with dilute hydrochloric acid. The precipitate is collected, washed with water and dried, obtaining 5 g of the epigraph compound, m.p. 257-258 ° C.

G) 5-Bromo-5- (4- (4-chloro-phenoxy) -phenyl) -pyrimidine-2,4,6-trione

Stir at room temperature for 3 hours. a suspension of the compound obtained in step F (6.3 g), N-bromo-succinimide (4.1 g) and dibenzoyl peroxide (100 mg) in carbon tetrachloride (120 ml). The mixture is concentrated by evaporation and the residue is extracted in ethyl acetate. The organic phase is dried and concentrated, yielding 7.5 g of the epigraphy compound in the form of oil viscous.

H) 5- (4- (4-Chloro-phenoxy) -phenyl) -5- (4-pyrimidin-2-yl-piperazine) -pyrimidine-2,4,6-trione

A solution of the compound of step G is treated (410 mg) in methanol (5 ml) with N- (pyrimidin-2-yl) -piperazine (330 mg). The mixture is stirred for 24 hours. The chromatography is residue, obtained after concentrating the reaction mixture by evaporation, through silica gel, using as eluent the 5% methylene chloride in methanol. The fractions meet relevant, obtaining 410 mg of the epigraphized compound in form solid amorphous, which is identified by mass spectroscopy: m / e = 492.

Example 2 5- [4- (4-Chloro-phenoxy) -phenyl] -5- (2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -pyrimidine-2,4,6- triona

The epigraphic compound is obtained so similar to that described in step H of example 1, using 330 mg of the 1- (pyrazin-2-yl) -piperazine instead of the N- (pyrimidin-2-yl) -piperazine, in this way 460 mg of the epigraphized compound is obtained in the form of amorphous product, which is identified by mass spectrometry: m / e = 492.

Example 3

The following compounds are obtained by applying the procedure described in example 1, but replacing the 4-chlorophenol for the corresponding phenols. The Final products are identified by mass spectrometry.

5

7

Example 4 4- (4-5- [4- (4-Chloro-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -N- (2-hydroxy -ethyl) -benzenesulfonamide TO) N- (2-hydroxy-ethyl) -4-piperazin-1-yl-benzenesulfonamide

Chloride dissolves 4-fluor-benzenesulfonyl in dichloromethane (20 ml) and treated with a solution of ethanolamine (1.2 ml) in dichloromethane (10 ml). The mixture is stirred for 1 hour. and extracted twice with water (50 ml). The aqueous phase is saturated with sodium chloride and extracted twice with ethyl acetate. They meet the organic phases are dried with magnesium sulfate and concentrated by evaporation 1.4 g of the 4-fluor-N-hydroxyethyl-benzenesulfonamide resulting in water (15 ml) and treated with piperazine (2.6 g). Be keep the mixture boiling at reflux for 6 hours and it kept at room temperature for 24 hours. The precipitated, washed with a little water and dried, obtaining 1.6 g of the epigraphy compound that is identified by spectrometry of masses (APCI) [M + H] = 286.

B) 4- (4-5- (4- (4-Chloro-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -N- (2-hydroxy -ethyl) -benzenesulfonamide

A solution of the compound of step G is treated of example 1 (230 mg) in methanol (5 ml) with n- (2-hydroxy-ethyl) -4-piperazin-1-yl-benzenesulfonamide (330 mg) (see before). The mixture is stirred for 24 hours. Be concentrate the reaction mixture by evaporation, chromatography the residue through silica gel with a mixture of chloride 15% methylene in methanol. The relevant fractions meet, obtaining 186 mg of the solid-shaped epigraph compound amorphous that is identified by mass spectrometry: APCI [M + 1] = 614

Example 5

The following compounds are obtained using the procedures of example 1, but replacing the 4-chlorophenol for the corresponding phenols, when it's requested. Piperazine derivatives are obtained with according to the procedure of step A of example 4, but replacing ethanolamine with the appropriate amine. The products Finals are identified by mass spectrometry.

8

9

10

eleven

Example 6 N- (2-oxo- [1,3] dioxolan-4-ylmethyl) -4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] -piperazin-1-yl-benzenesulfonamide

Product No. 11 of Example 5 is dissolved (120 mg) in a mixture of dichloromethane (5 ml) and tetrahydrofuran (5 ml). The solution is treated with N, N'-carbonyl diimidazole (65 mg) and stir at room temperature for 4 h. The solvent and the residue is chromatographed through silica gel, using a 9/1 dichloromethane / methanol mixture as eluent. Be evaporate the fractions containing product, obtaining 60 mg of the epigraph compound, mass spectrum: APCI [M + H] = 636; [M-H] = 634.

Example 7 N- (4-amino-butyryl) -4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] -piperazin-1-yl-benzenesulfonamide TO) 4- (4-benzyl-piperazin-1-yl) -benzenesulfonamide

Chloride dissolves 4-fluorbenzenesulfonyl (25 g) in dichloromethane (250 ml) and treated at 0 ° C with an aqueous solution of ammonia (25%, 50 ml) The mixture is stirred for 2 h with cooling and at temperature One night atmosphere. The reaction mixture is acidified and evaporate the organic solvent. The residue is extracted with acetate ethyl, obtaining 20 g of the 4-fluorbenzenesulfonamide, which dissolves in water (300 ml), is treated with 1-benzyl-piperazine (102 g) and be kept at reflux for 24 h. The reaction mixture is filtered, obtaining 26 g of the epigraph compound (mass spectrum, APCI [M + H] = 332).

B) 4- [4- (piperazin-1-yl) -benzenesulfonylamino] -4-oxo-butyl-carbamate tert-butyl

The acid dissolves 4- (N-tert-butoxycarbonyl) -aminobutyric acid (3.05 g) in tetrahydrofuran (30 ml) and treated with N, N'-carbonyldiimidazole (2.5 g). The mixture is stirred at room temperature for 15 min, it is heated to reflux for 15 min and stir at room temperature for 1 hour. The product of step A (3.3 g) and the mixture is stirred for one night. The solvent is evaporated and the residue is mixed with dichloromethane and water. The organic phase is separated, dried and dried. evaporate the solvent. The residue is chromatographed through gel. of silica using as eluent a 9/1 mixture of dichloromethane / methanol. The residue is subjected to hydrogenation catalytic in methanol, using Pd on carbon as catalyst, in this way 2.5 g of the epigraph compound is obtained, spectrum APCI mass [M-H] = 425.

C) N- (4-amino-butyryl) -4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] -piperazin-1-yl-benzenesulfonamide

The compound obtained in the reaction is reacted stage B similarly to that described in stage H of example 1 with the 5-Bromo-5- (4- (phenoxy) -phenyl) -pyrimidine-2,4,6-trione. This last compound is obtained in a similar way to that described in the example 1, substituting p-chlorophenol for phenol. To remove the BOC protective group the product is dissolved (290 mg) in a 4N solution of HCl in dioxane. After 1 hour at room temperature the solution is decanted and the residue is crushed with ether, obtaining 180 mg of the epigraph compound, spectrum of APCI masses [M + H] = 621.

Example 8

The following compounds are obtained by applying the procedures of example 7, but replacing the acid 4- (N-tert-butoxycarbonyl) -amino-butyric by the appropriate amino acid protected on N with the group tert-butoxycarbonyl. The final products are identified by mass spectrometry.

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Example 9 2-oxo-2- (4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] -piperazin-1-yl-benzenesulfonylamino) -ethyl] -carbamate 4-methoxy-phenyl

Product # 1 of Example 5 is dissolved (140 mg) in dichloromethane (10 ml), mixed with triethylamine (0.14 ml) and It is treated with 4-methoxyphenyl chloroformate. Be Stir the mixture at room temperature for 90 min and concentrate by evaporation The residue is chromatographed through gel silica using as eluent a 9/1 mixture of dichloromethane / methanol. The relevant fractions meet, obtaining 90 mg of the epigraph compound, APCI mass spectrum [M + H] = 743.

Example 10

In order to determine the inhibition of MMPs, for example of HNC (MMP-8), the catalytic domain is incubated (isolation and purification, see for example Schnierer, S., Kleine, T., Gote, T., Hillemann, A., Knauper, V., Tschesche, H., in Biochem. Biophys. Res. Commun. 191 , 319-326, 1993) with various concentrations of inhibitors. The initial reaction rate of the conversion on a standard substrate is then measured, similar to that described by Grams, F. et al., FEBS 335 , 76-80, 1993.

The results are evaluated by plotting the rate of reciprocal reaction against the concentration of the inhibitor. The inhibition constant (Ki) is obtained from the negative section of the abscissa by the graphic method proposed by Dixon, M., in Biochem. J. 55 , 170-202, 1953.

The synthetic collagenase substrate is a heptapeptide that binds, at its end C, with the DNP (dinitrophenol). Said DNP remainder reduces by steric hindrance the fluorescence of the adjacent tryptophan in the heptapeptide. After of the decomposition with detachment of a tripeptide that includes the DNP group, increases the fluorescence of tryptophan. By therefore, the proteolytic decomposition of the substrate can be measured through the fluorescence value.

a) First method

The test is carried out at 25 ° C in a buffer Freshly prepared 50 mM Tris (pH 8.0), treated with dithiozone for remove traces of heavy metals. 4 mM CaCl2 is added and the buffer is saturated with argon. Standard solutions of the adamalisin II by centrifugation of the protein in a suspension of ammonium sulfate and subsequent dissolution in the assay buffer. Be dilute the collagenase standard solutions with the buffer of test. Enzyme concentrations are determined by measurements UV (ε 280 = 2.8.10 4 M -1 .cm -1; ε 288 = 2.2.10 4 M -1 .cm -1) and the Standard solutions are stored cold. This solution is diluted in 1: 100 ratio to obtain the final 16 nM concentration of test. The fluorogenic substrate is used DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH_ {2}  with a Km of 52 µM in a concentration of 21.4 µM; for the determination of the K_ {i} a 12.8 µM concentration. Substrate fluorescence is measured at an excitation wavelength λ = 320 and emission λ = 420 nm, respectively, in a spectrofluorimeter (Perkin Elmer, model 650-40), equipped with a thermostated cell holder. The hydrolysis is monitored of the substrate for 10 min. immediately after adding the enzyme. All reactions are carried out at least by triplicate. The Ki values of the inhibitors a are calculated from the point of intersection of the straight lines obtained by graphical representation of the values v_ {o} / v_ {i} against the [concentration of the inhibitor], while the IC 50 values are calculated from the curves v_ {o} / v_ {i} [concentration of inhibitor] by non-linear regression by weighting robust and simple.

b) Second method

test buffer:

50 mM Tris / HCl, pH 7.6 (Tris = tris- (hydroxymethyl) -aminomethane)

100 mM NaCl / 10 mM CaCl2 in 5% MeOH (yes if necessary)

enzyme: 8 nM catalytic domain (Met80-Gly242) of human neutrophil collagenase (MMP-8)

substrate: 10 microM of DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH_ {2}

total test volume: 1 ml.

A solution of the enzyme and the inhibitor in assay buffer (25 ° C). Reaction starts introducing the substrate into the solution. The tracking of decomposition with evolution of the fluorogenic substrate by fluorescence spectroscopy with wavelengths of excitation and emission of 280 and 350 nm, respectively. The value IC 50 is calculated as the concentration of the inhibitor that is necessary to decrease the reaction rate to half of the value it has in a reaction without inhibitor.

Table 1 shows the IC50 values. found and compared with the compounds of example 26 and with the Preferred compound No. 118 cited in the patent application EP-0869947.

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TABLE 1

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Claims (7)

1. Compounds of the formula

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14 in the that R 1 means a phenoxy moiety, in which the phenyl group may be substituted by one or more atoms of halogen, hydroxy groups, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, cyano or nitro; Y R2 means pyrimidine, pyrazine or its N-oxides or phenyl substituted by -SO 2 NR 3 R 4, in which R 3 and R 4 are same or different and mean hydrogen; I rent C 1 -C 6, straight or branched chain, which may be substituted once or several times by OR, N (CH 3) 2 or which may be interrupted by oxygen; or means COR_ {5}, in which R_ {5} is a group alkyl that may be substituted by NH2. 2. Compounds of formula I according to claim 1, wherein R1 is phenoxy substituted one or several times by chlorine, bromine, methyl or tert-butyl. 3. Compounds of formula I according to claim 1, wherein R 3 means hydrogen and R 4 means hydrogen, -CH2CH2OH; -CH 2 CH 2 -N (CH 3) 2; -CH 2 -CH (OH) -CH 2 OH; -CH (CH 2 OH) 2; -CH 2 -CH 2 -O-CH 2 CH 2 -O-CH 2 CH 2 OH; or -C (CH 2 OH) 3. 4. Compounds of formula I according to claim 1, chosen from the group consisting of: 5- (4- (4-Chloro-phenoxy) -phenyl) -5- (4-pyrimidin-2-yl-piperazine) -pyrimidine-2,4,6-trione 5- [4- (4-Chloro-phenoxy) -phenyl] -5- (2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -pyrimidine-2,4,6- triona 5- [4- (3,4-Dichloro-phenoxy) -phenyl] -5- (4-pyrimidin-2-yl-piperazin-1-yl) -pyrimidine-2,4,6-trione 5- [4- (3,4-Dichloro-phenoxy) -phenyl] -5- (2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -pyrimidine-2,4, 6-triona 5- [4- (4-Bromo-phenoxy) -phenyl] -5- (4-pyrimidin-2-yl-piperazin-1-yl) -pyrimidine-2,4,6-trione 4- (4-5- [4- (4-Chloro-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -N- (2-hydroxy -ethyl) -benzenesulfonamide 4- (4-5- [4- (4-Bromo-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -benzenesulfonamide 4- (4-5- [4- (4-Bromo-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -N- (2-dimethylamino -ethyl) -benzenesulfonamide 4- (4-5- [4- (4-Bromo-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -benzenesulfonamide 4- (4-5- [4- (4-Chloro-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -N, N-bis- (2-hydroxy-ethyl) -benzenesulfonamide N- (2,3-dihydroxy-propyl) -4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] -piperazin-1-yl- benzenesulfonamide N- (2-hydroxy-1-hydroxymethyl-ethyl) -4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] -piperazin-1- il-benzenesulfonamide N-2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethyl-4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl ] -piperazin-1-yl-benzenesulfonamide N- (2-hydroxy-1,1-bis-hydroxymethyl-ethyl) -4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] - piperazin-1-yl-benzenesulfonamide 4- (4-5- [4- (4-Chloro-phenoxy) -phenyl] -2,4,6-trioxo-hexahydro-pyrimidin-5-yl-piperazin-1-yl) -N- (2-hydroxy -1,1-bis-hydroxymethyl-ethyl) -benzenesulfonamide N- (2-oxo- [1,3] dioxolan-4-ylmethyl) -4-4- [2,4,6-trioxo-5- (4-phenoxy-phenyl) -hexahydro-pyrimidin-5-yl] -piperazin-1-yl-benzenesulfonamide. 5. Pharmaceutical compositions that, like active ingredient, contain a compound according to claims 1 to 4 in combination with excipients or pharmaceutically acceptable diluents. 6. Use of compounds according to the claims 1 to 4 for the manufacture of a drug that has activity metalloproteinase inhibitor. 7. Use of compounds according to claim 6 that have antitumor and / or antimetastatic activity.